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DOCK8缺失通过迁移引起的细胞破碎导致2型偏向的辅助性T细胞反应
作者:小柯机器人 发布时间:2020/10/10 13:53:09

近日,加拿大麦吉尔大学Judith N. Mandl及其小组发现,DOCK8缺失通过迁移引起的细胞破碎导致2型偏向的辅助性T细胞反应。相关论文于2020年10月5日在线发表在《自然—免疫学》杂志上。

研究人员证明,与人类一样,Dock8-/-小鼠在肺部感染隐球菌和其他非2型辅助性T(TH2)刺激物后,也具有显著的CD4+TH2细胞偏向。研究人员发现招募的Dock8-/-CX3CR1+单核吞噬细胞对迁移诱导的细胞破碎非常敏感,从而释放出白介素(IL)-1β,后者驱动CD4+T细胞产生粒细胞-巨噬细胞集落刺激因子(GM-CSF)。阻断IL-1β、GM-CSF或caspase活化可消除缺乏Dock8的小鼠的2型偏向。
 
值得注意的是,用凋亡细胞治疗感染的野生型小鼠显著增加了GM-CSF的产生和TH2细胞的分化。这揭示了细胞死亡在感染期间驱动2型信号中的重要作用,可能有助于理解变态反应性疾病中2型CD4+T细胞反应的病因。
 
据介绍,影响免疫细胞迁移并导致免疫缺陷的突变说明了细胞运动在宿主防御中的重要性。在人类中,参与造血细胞迁移的鸟嘌呤交换因子DOCK8的功能丧失突变会导致免疫缺陷,但也导致过敏性疾病。
 
附:英文原文

Title: Migration-induced cell shattering due to DOCK8 deficiency causes a type 2–biased helper T cell response

Author: Caitlin Schneider, Connie Shen, Angelica A. Gopal, Todd Douglas, Benjamin Forestell, Keith D. Kauffman, Dakota Rogers, Patricio Artusa, Qian Zhang, Huie Jing, Alexandra F. Freeman, Daniel L. Barber, Irah L. King, Maya Saleh, Paul W. Wiseman, Helen C. Su, Judith N. Mandl

Issue&Volume: 2020-10-05

Abstract: Mutations that impact immune cell migration and result in immune deficiency illustrate the importance of cell movement in host defense. In humans, loss-of-function mutations in DOCK8, a guanine exchange factor involved in hematopoietic cell migration, lead to immunodeficiency and, paradoxically, allergic disease. Here, we demonstrate that, like humans, Dock8−/− mice have a profound type 2 CD4+ helper T (TH2) cell bias upon pulmonary infection with Cryptococcus neoformans and other non-TH2 stimuli. We found that recruited Dock8−/−CX3CR1+ mononuclear phagocytes are exquisitely sensitive to migration-induced cell shattering, releasing interleukin (IL)-1β that drives granulocyte−macrophage colony-stimulating factor (GM-CSF) production by CD4+ T cells. Blocking IL-1β, GM-CSF or caspase activation eliminated the type-2 skew in mice lacking Dock8. Notably, treatment of infected wild-type mice with apoptotic cells significantly increased GM-CSF production and TH2 cell differentiation. This reveals an important role for cell death in driving type 2 signals during infection, which may have implications for understanding the etiology of type 2 CD4+ T cell responses in allergic disease. Humans with inherited defects in DOCK8 expression are prone to allergic, type 2 CD4+ T cell responses. Mandl and colleagues reveal an important role for cell death in driving such type 2 signals during infection.

DOI: 10.1038/s41590-020-0795-1

Source: https://www.nature.com/articles/s41590-020-0795-1

期刊信息

Nature Immunology:《自然—免疫学》,创刊于2000年。隶属于施普林格·自然出版集团,最新IF:23.53
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex